Background: The scene of a mass-casualty attack (MCA) entails a crime scene, a hazardous space and a great number of people needing medical assistance. Public transportation has been the target of such attacks and involves a high probability of generating mass casualties. The aim of the review was to investigate challenges for on-scene responses to MCAs and suggestions made to counter these challenges, with special attention given to attacks on public transportation and associated terminals. Methods: Articles were found through PubMed and Scopus, “relevant articles” as defined by the databases, and a manual search of references. Inclusion criteria were that the article referred to attack(s) and/or a public transportation-related incident and issues concerning formal on-scene response. An appraisal of the articles’ scientific quality was conducted based on an evidence hierarchy model developed for the study. Results: One hundred and five articles were reviewed. Challenges for command and coordination on scene included establishing leadership, inter-agency collaboration, multiple incident sites, and logistics. Safety issues entailed knowledge and use of personal protective equipment, risk awareness and expectations, dynamic risk assessment, cordons, defensive versus offensive approaches, and joining forces. Communication concerns were equipment shortfalls, dialoguing and providing information. Assessment problems were scene layout and interpreting environmental indicators as well as understanding setting-driven needs for specialist skills and resources. Triage and treatment difficulties included differing triage systems, directing casualties, uncommon injuries, field hospitals, level of care and providing psychological and pediatric care. Transportation hardships included scene access, distance to hospitals, and distribution of casualties. Conclusion: Commonly encountered challenges during unintentional incidents were augmented during MCAs, implying specific issues for safety, assessment, triage, and treatment, which require training. Effectively increasing readiness for MCAs will likely entail struggles to overcome fragmentation between the emergency services and the broader crisis management system as well as enabling critical and prestige-less, context-based assessments, of needed preparatory efforts.